Seminars in Oncology
Volume 32, Issue 3 , Pages 315-328, June 2005

Current Management of Advanced Non-Small Cell Lung Cancer: Targeted Therapy

  • Takeshi Isobe
    • ,
  • Roy S. Herbst
    • ,
  • Amir Onn

      Affiliations

    • Corresponding Author InformationAddress reprint requests to Amir Onn, MD, Department of Pulmonary Medicine, Unit 403, The University of Texas M.D. Anderson Cancer Center, 1515 Holcombe Blvd, Houston, TX 77030

Departments of Thoracic/Head and Neck Medical Oncology, Pulmonary Medicine, and Cancer Biology, The University of Texas M.D. Anderson Cancer Center, Houston, TX

Article Outline

Lung cancer is one of the most frequent causes of cancer-related death in the United States. For patients with advanced non-small cell lung cancer (NSCLC), chemotherapy, alone or in combination with radiation therapy, is considered the standard treatment. Although this treatment may result in a modest improvement in patient survival, overall prognosis of these patients remains dismal, and the treatment is nonspecific, nonselective, and toxic. Therefore, new therapeutic strategies are needed. During the past decade, several molecules that contribute to lung cancer progression and metastasis have been identified. Growth factors and proangiogenic factors have been the focus of intense research in cancer since therapeutic approaches for their inhibition do exist. The role of these factors was studied in different organs and tumors and was found to be phenotypically distinct. Several molecular targeted therapies have shown efficacy and had been approved for treatment of specific cancers. Most advanced in clinical research for lung cancer are targeted therapies that inhibit the epidermal growth factor receptor (EGFR) and the vascular endothelial growth factor (VEGF) signaling pathways. Others are signaling pathway inhibitors. The first targeted therapy for lung cancer is gefitinib, an EGFR inhibitor, which was approved in several countries in 2003. Goals of molecular targeted therapy studies include the following: better understanding of the exact role of particular growth factors in specific tumors; establishment of new clinical study designs for biological agents; and tailoring appropriate combinations of conventional chemotherapy and/or radiotherapy with biological therapy for specific patients. Achievement of these goals will hopefully lead to incorporation of biological therapy into the current anticancer arsenal, for the benefit of lung cancer patients.

 

Lung cancer remains the leading cause of cancer-related death in the United States.1 Approximately 80% of lung carcinomas are non-small cell lung cancers (NSCLCs). Unfortunately, most new cases of NSCLC are locally advanced or metastatic at presentation, and the prognosis for these patients is generally poor. Chemotherapy, alone or in combination with radiation therapy, is the standard treatment for advanced NSCLC.

Randomized studies conducted over the past decade have shown that cisplatin-based chemotherapy provides a survival advantage over supportive care alone, two-drug chemotherapy regimens are superior to single-agent regimens, and two-drug combinations should contain at least one new agent (paclitaxel, docetaxel, gemcitabine, vinorelbine, or irinotecan).2 However, improvements in chemotherapy for advanced NSCLC have reached a plateau; there are few differences among the various combinations of drugs, and these treatments are nonspecific, nonselective, and toxic.

Advances in our understanding of cancer biology have led to the discovery of several potential molecular targets and the development of novel agents that, unlike conventional cytotoxic agents, specifically target tumor cells.3, 4 Two such therapies are imatinib, a small-molecule inhibitor of the intracellular tyrosine kinase (TK) BCR-ABL approved by the US Food and Drug Administration for the treatment of chronic myeloid leukemia in 2001, and the monoclonal antibody trastuzumab, which targets a membrane-bound growth factor receptor and was approved in 1998 for the treatment of metastatic breast cancer. The concept of more specific targeting of tumor cells or their blood vessels has been termed “molecular targeted therapy.”

Another treatment approach is to block the tumor’s blood supply, thus preventing oxygen and nutrients from reaching the tumor. The growth of new capillaries, or angiogenesis, is required for tumor growth and metastasis. Tumor angiogenesis is dependent on the proliferation and migration of endothelial cells. Therefore, not only tumor cells but also tumor vascular endothelial cells have become an important target in cancer therapy. In addition, endothelial cells are genetically stable and thus are less likely to accumulate mutations that enable them to acquire drug-resistant phenotypes. These potentially therapeutic advantages are why endothelial cells are the focus of extensive investigations in antiangiogenic (ie, anti newly formed blood vessels) and antivascular (ie, anti pre-existing vasculature) therapy.5, 6

Most advanced in clinical research for NSCLC are targeted therapies that inhibit the epidermal growth factor receptor (EGFR) (Fig 1) and the vascular endothelial growth factor (VEGF) signaling pathways. In fact, the first targeted therapy for NSCLC is gefitinib; an EGFR tyrosine kinase inhibitor (TKI) approved in many countries, including the United States, Canada, Australia, and Japan. This article will review the role, efficacy, and safety of targeted agents in the treatment of advanced NCSLC (Table 1).

  • View full-size image.
  • Figure 1. 

    Representative samples of immunofluorescent histology of CD31 and EGFR in human adenocarcinoma of the lung. (A) Double-labeling for CD31 and EGFR to study expression of receptor on tumor-associated endothelial cells. (B) EGFR expression on tumor cells. Red: CD31+ endothelial cells; green: EGFR+ cells; yellow: EGFR+ endothelial cells (arrows); blue: nuclear staining (original magnification, ×400). In this particular tumor, both tumor cells and tumor-associated endothelial cells express EGFR.

Table 1. Targeted Therapy for Non-Small Cell Lung Cancer
TargetAgentStructureComment
EGFRCetuximab (Erbitux)MabChimeric IgG Mab
Gefitinib (Iressa)SMKIQuinazoline, reversible
Erlotinib (Tarceva)SMKIQuinazoline, reversible
CI1033SMKIQuinazoline, irreversible
Her2Trastuzumab (Herceptin)MabHumanized monoclonal antibody
RasTipifarnibFTINon-peptidomimetic quinolone
LonafarnibFTINon-peptidomimetic, reversible
BMS214662FTIBenzodiazepine
MMPPrinomastatMMPIMMP-2 and MMP-9 inhibitor
BMS275291MMPIMMP-1, -2, -8, -9, -13, -14 inhibitor
NeovastatMMPIAnti-VEGF and MMPI
PKCISIS3521ASO
RARBexarotene Synthetic retinoid analog
VEGFBevacizumab (Avastin)MabHumanized Mab
SemaxanibSMKIVEGFR-2 inhibitor
SU6668SMKIVEGFR-1, PDGF, and bFGFR inhibitor
ZD6474SMKIVEGFR-2 and EGFR inhibitor
ZD6126 Disruption of the cytoskeleton of tumor EC
AngiogenesisEndostatin Cleavage product of plasminogen

Abbreviations: EGFR, epidermal growth factor receptor; Mab, monoclonal antibody; SMKI, small molecule kinase inhibitor; FTI, farnesyl transferase inhibitor; MMP, matrix metaloproteinase; MMPI, MMP inhibitor; VEGF, vascular endothelial growth factor; PKC, protein kinase C; ASO, anti-sense oligonucleotide; RAR, retinoic acid receptor; VEGFR, VEGF receptor; PDGF, platelet-derived growth factor; bFGF, basic fibroblast growth factor receptor; EC, endothelial cell.

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EGFR Inhibitors 

The EGF family of receptors shares a common molecular structure that consists of an amino-terminal extracellular domain, a single transmembrane-anchoring region, and a carboxyl-terminal intracellular domain that has TK activity.7 Binding of ligands to the extracellular domain of EGFR activates the receptor and its signaling pathways, which results in the orchestrated activation or modulation of cellular processes such as proliferation, differentiation, migration, and survival.8 Many molecules have been identified that can specifically bind and activate the EGF family of receptors. For example, EGF and transforming growth factor-α bind to EGFR, whereas no specific ligand has been identified for HER2. The binding of ligands to the receptor induces the formation of either homodimers or heterodimers of EGFR with other members of the family. It is interesting that the transforming potential and the signaling pathway activated by the different dimers are not the same. EGFR-HER2 heterodimers are associated with a more intense and sustained proliferative signal than are EGFR homodimers, and the lack of a specific ligand for HER2 is evidence that HER2 potentiates receptor signaling by heterodimerizing with other members of the EGF family. Dimerization induces conformational changes in EGFR that result in intracellular TK moiety activation and receptor autophosphorylation, which leads to the formation of intracellular docking sites for cytoplasmic amplifying molecules that contain Src homology 2 domains or phosphotyrosine-binding sites. These molecules then activate a multitude of signal transduction molecules. Among the many pathways activated by EGFR are the mitogen-activated protein kinase pathway, which regulates gene transcription and proliferation, and the phosphatidylinositol-3-kinase signaling pathway, which mediates cell survival.8

EGFR expression in tissue samples can be evaluated by analyzing the levels of protein (immunohistochemical tests, Western blotting, or enzyme immunoassay), RNA (Northern blotting and reverse transcription polymerase chain reaction), or DNA (fluorescence-in-situ hybridization or quantitative polymerase chain reaction). The technique most commonly used is immunohistochemical testing because reagents and equipment are widely available and it allows direct evaluation of the target. However, the technique has still not been standardized.

The rationale for EGFR inhibition as a target for cancer therapy was proposed nearly 20 years ago, by Mendelsohn and collaborators, who noted that the EGFR is frequently overexpressed in human tumors, and in many cases is associated with poor outcome.3 The rate of EGFR overexpression in NSCLC ranges from 43% to 89% (Table 2).9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24 Differences in reported data on EGFR expression most likely reflect differences in techniques, procedures, antibodies, definitions of positive EGFR expression, and study populations. The molecular mechanism responsible for overexpression of EGFR is not fully understood; EGFR gene amplification has been found in only a minority of NSCLC cases.25 Results of studies correlating EGFR expression in NSCLC and patient survival have shown conflicting results (Table 2). A meta-analysis of 11 studies (2,185 patients) showed that EGFR expression was not a prognostic factor for survival in NSCLC.26

Table 2. Effect of EGFR Expression on Survival in Non-Small Cell Lung Cancer
First Author (year)No. of PatientsStageEGFR + Rate (%)Effect on Survival
TotalSCCAC
Dazzi (1989)9152I-IV495545NS
Tateishi (1994)10119I-IV46NI46NS
Pastorino (1997)11515I47NRNRNS
Rusch (1997)1296I-IIIA709257NS
Greatens (1998)13101I-IV89NRNRNS
Pfeiffer (1998)14186I-IV55NRNRNS
Volm (1998)15121I-III8383NIReduced survival
Fontanini (1998)16195I-IIIA815735NS
Fu (1999)17158I-IIIB66NRNRNS
D’Amico (1999)18408I52NRNRNS
Ohsaki (2000)19290I-IV435137Reduced survival
Cox (2000)20169I-IIIA566828NS
Lai (2001)2173I666865Reduced survival
Kanematsu (2003)2236I-IV817982NS
Hirsch (2003)23183I-III628240NS
Onn (2003)24110I607447NS

Abbreviations: EGFR, epidermal growth factor receptor; SCC, squamous cell carcinoma; AC, adenocarcinoma; NS, not statistically significant; NI, not included; NR, not recorded.

EGFR also exists in a mutant form, EGFRvIII, which is the result of a 267-amino acid in-frame deletion and insertion of a glycine in the fusion junction of the extracellular domain. This mutation, detected in about 15% of NSCLCs as well as in other solid tumors, leads to ligand-independent constitutive TK activity and altered subcellular localization of the receptor, and it may confer resistance to chemotherapy.27

On the basis of these molecular characteristics of NSCLC, several agents have been developed that target the erbB-receptor family, including monoclonal antibodies that compete with the ligands for the extracellular domain of the receptor, small-molecule inhibitors of the intracellular TK domain of the receptor, antisense oligonucleotides that reduce the level of EGFR, and inhibiting downstream effectors of the EGFR signaling network. Anti-EGFR monoclonal antibodies and small-molecule inhibitors of EGFR TK activity are the most important of these agents because they have been extensively investigated in clinical trials.

In two pivotal studies, Lynch et al28 and Paez et al29 recently discovered gain-of-function somatic mutations of EGFR in exons 18–21 and correlated them with response to EGFR inhibitors.

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Anti-EGFR Monoclonal Antibodies 

Cetuximab is a chimeric IgG monoclonal antibody directed against the extracellular ligand-binding domain of HER1. Preclinical studies have shown that cetuximab binds to HER1 at a higher affinity (Kd = 0.1 nmol/L) than do the major ligands, EGF and transforming growth factor-α. When cetuximab binds to HER1, it decreases ligand-induced activation of receptor TK activity, inhibiting the effects of HER1 signaling and stimulating receptor internalization. The antitumor efficacy of cetuximab results from multiple mechanisms, including inhibition of angiogenesis, promotion of apoptosis, and enhancement of immunologic activity.30, 31 Cetuximab has a half-life of approximately 7 days and can be given weekly as a loading dose of 400 mg/m2 followed by a maintenance dose of 250 mg/m2. Side effects include acne-like skin rash, asthenia, and allergic reactions, which occur in ≤4% of cases. No gastrointestinal side effects have been observed in preclinical NSCLC models, and cetuximab has been shown to potentiate the effects of chemotherapy and radiation therapy.30, 31 Phase II trials of cetuximab combined with gemcitabine and carboplatin,32 paclitaxel and carboplatin,33 and single-agent docetaxel34 in patients with NSCLC have all shown that cetuximab can be safely combined with chemotherapy. In the two first-line therapy trials, the response rates did not appear to be higher than would be expected with chemotherapy alone.32, 33 In the second-line setting, cetuximab and docetaxel resulted in a 22.3% overall response rate, but the median survival was only 7.5 months.34 A small randomized phase II trial compared vinorelbine and cisplatin alone and with cetuximab as first-line treatment of NSCLC. Overall response rates favored the cetuximab group (53.3% v 32.2%), as did disease control rates (93.3% and 77.4%).35 Overall preliminary phase II data suggest that cetuximab enhances the benefit of combination chemotherapy in chemotherapy-naive patients with NSCLC.32, 33, 36

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Inhibitors of EGFR TK Activity 

Gefitinib and erlotinib are small molecules that reversibly target HER1 TK. In phase I studies, both have resulted in objective responses in heavily pretreated patients with NSCLC when used as single agents.37, 38 They are well absorbed after oral administration and can be given long term. The drugs’ side effects are usually mild to moderate and consist of dose-dependent rash and diarrhea, which represent the dose-limiting toxicities (DLTs).

The bioavailability of orally administered gefitinib is 59%; it has a terminal half-life of 28 hours and can be administered once daily. A pharmacokinetic analysis in a phase I trial showed that the steady-state concentrations of gefitinib were achieved by day 7 of administration. In a phase I study of erlotinib evaluating several administration schedules, a mean half-life of 24.4 hours at the 150-mg/d dosage was documented.38

Two randomized phase II multicenter trials (Dose Evaluation in Advanced Lung Cancer 1 and 2) with two dosages (250 and 500 mg/d) of gefitinib were conducted in more than 400 patients with stage III or IV NSCLC whose disease had failed to respond to platinum-based chemotherapy.39, 40 Side effects were generally mild and consisted of rash, pruritus, and diarrhea, but they were significantly more common and severe at the higher dosage. In neither trial were there significant differences in efficacy variables between the 250- and 500-mg/d dosages. Thus, the recommended dosage for patients with NSCLC who previously have undergone platinum-based chemotherapy is 250 mg/d. On the basis of these studies, gefitinib has been approved for use in NSCLC in several countries.41

Erlotinib was investigated in a phase II trial in 56 patients with advanced NSCLC whose disease had failed to respond to platinum-based chemotherapy.38 Unlike in gefitinib studies, patients were included only if they had overexpression of EGFR (>10% positive cells). In this study, erlotinib was given continuously at a fixed dosage of 150 mg/d, which produced an acneiform rash in 78% of patients. Twelve percent of patients responded to erlotinib, and 39% of patients had prolonged stable disease during the treatment.38

Gefitinib and erlotinib do not induce myelosuppression, which makes them appealing for use with chemotherapy. The results of two large, randomized, placebo-controlled, phase III trials (Iressa NSCLC Trial Assessing Combination Treatment [INTACT]; trials 1 [gemcitabine and cisplatin] and 2 [paclitaxel and carboplatin]) of gefitinib in chemotherapy-naive patients with stage IIIB/IV NSCLC have been reported.42, 43 Patients were randomly assigned to receive either placebo, 250 mg/d of gefitinib, or 500 mg/d of gefitinib in addition to chemotherapy. Patients continued with gefitinib or placebo until disease progression. Results showed that gefitinib did not yield additional therapeutic benefits over chemotherapy alone. However, there did appear to be a maintenance effect of gefitinib in patients with NSCLC who responded to chemotherapy, suggesting a role for sequencing and maintenance therapy.43 Two large randomized trials with chemotherapy with or without erlotinib have been completed. Similar to the phase III studies of gefitinib in combination with chemotherapy, erlotinib in concurrent combination with carboplatin and paclitaxel (the TRIBUTE study; N = 1,059) or with cisplatin and gemcitabine (TALENT; N = 1,172) did not confer a survival advantage over chemotherapy alone in patients with previously untreated advanced NSCLC.44, 45

The National Cancer Institute of Canada conducted a multicenter randomized placebo-controlled trial of erlotinib (150 mg/d) in patients with advanced NSCLC following failure of first-line or second-line chemotherapy (trial BR.21). Results on this study involving 731 patients were presented at the ASCO 2004 meeting, and showed—for the first time in a randomized trial—that single-agent erlotinib prolonged survival in patients after first- or second-line chemotherapy. Overall response to erlotinib was 9%, and the overall survival was 6.7 months for erlotinib versus 4.7 months for placebo (P = .001).46 Based on these data, erlotinib received approval by the US Food and Drug Administration in November 2004.

Retrospective analyses of gefitinib39, 40 or erlotinib47 studies revealed several clinical predictors of response. These studies showed that responses were more frequent among patients who had never smoked, women, patients with adenocarcinomas, and patients with East Asian ethnicity. Dramatic advances in EGFR mutations research have been presented in recent months. These studies suggested that EGFR mutations in exons 18–21 account for the increased sensitivity of NSCLC patients to EGFR small molecule tyrosine kinase inhibitors. Furthermore, patients who did not express a mutation had a low probability of responding.28, 29 The group from Memorial Sloan-Kettering Cancer Center extended these data and showed that similar EGFR mutations are also associated with responses to erlotinib.47 These findings are supported by a report on a correlation between clinical predictors of response mentioned above and EGFR mutation status.48 Compiling these data reveals that EGFR mutations are identified in 80% of responders to EGFR small molecule tyrosine kinase inhibitors, whereas mutations in K-ras (exon 2) are associated with lack of sensitivity to either erlotinib or gefitinib.47

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HER2 Inhibition 

Trastuzumab is a recombinant DNA-derived humanized monoclonal antibody based on human IgG. It binds HER2 receptors, which, when activated, alter several downstream signals, especially the mitogen-activated protein kinase pathways, causing cell cycle arrest in the G0 to G1 phase.49

The ECOG conducted a phase II study of trastuzumab in 139 patients with NSCLC.50 Patients received trastuzumab plus paclitaxel and carboplatin. The overall response rate was 24.5%, median progression-free survival was 3.3 months, median overall survival was 10.1 months, and the 1-year overall survival rate was 42%. To further evaluate the effect of trastuzumab, a multicenter randomized trial was conducted using gemcitabine and cisplatin with or without trastuzumab.51 In the M.D. Anderson Cancer Center study, 20 previously untreated patients achieved a partial response rate of 40%, and 45% had stable disease.52 Further studies are required to determine the role of trastuzumab in NSCLC. However, the modest levels of gene amplification and HER2 expression in NSCLC limit further development of this drug.

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Farnesyl Transferase Inhibitors 

Farnesyl transferase inhibitors (FTIs) are compounds designed to interfere with signal transduction in cancer cells containing ras gene mutations. Ras genes encode Mr 21,000 proteins that are intermediates in the signal transduction pathways critical for cellular processes such as growth, differentiation, and apoptosis. Oncogenic ras mutations have been identified in approximately 30% of human cancers (in particular, they have been found in 40% of NSCLC cases) and are considered to be poor prognostic factors.53 The enzyme FT catalyzes the first step in the posttranslational modification of a number of guanine-nucleotide binding proteins involved in cell signaling. FT initially attracted attention because of its role in the processing of ras proteins, which transduce receptor and nonreceptor TK activation to downstream cytoplasmic and nuclear effectors. Activating mutations in ras proteins results in constitutive signaling, leading to cell proliferation and inhibition of apoptosis.54 Oncogenic ras protein function is dependent on localization to the plasma membrane. A critical step in ras localization is posttranslational modification through the addition of a farnesyl group to the COOH terminus of the protein. This process is called farnesylation and is catalyzed by FT.

There are currently three FTIs undergoing active clinical testing. These agents belong to the non-thiol, nonpeptidomimetic heterocyclic class of small-molecule inhibitors. Two of these, tipifarnib and lonafarnib, are orally bioavailable, whereas BMS214662 is administered intravenously. These three FTIs are well tolerated, and toxicities are generally reversible. Schedule-dependent myelosuppression, gastrointestinal effects, and fatigue were the DLTs in phase I trials. Combination regimens tested have been active and well tolerated, and the FTIs did not demonstrate significant pharmacokinetic interactions with standard cytotoxic agents.55 The combinations of chemotherapy drugs and tipifarnib or lonafarnib are now under evaluation in phase III trials in advanced NSCLC. Interim data analysis of the lonafarnib trial concluded that the study would not provide sufficient evidence of efficacy to warrant further enrollment.56

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Matrix Metalloproteinase Inhibitors 

Matrix Metalloproteinases (MMPs) are zinc-dependent proteases that belong to a family of endopeptidases. MMPs degrade the extracellular matrix and basement membrane, which is one of the first steps in angiogenesis. Increased expression of MMPs has been strongly implicated in tumor growth, invasion, and metastasis.57 MMPs are expressed by tumor, stromal, and proliferating endothelial cells, and in vitro models suggest that MMPs may play a direct role in angiogenesis through interactions with VEGF and integrins. Overexpression of MMPs in tumors and their surrounding stroma appears to increase as tumors dedifferentiate and metastasize, and increased MMP expression has been shown to be associated with a worse overall prognosis in many malignancies, including NSCLC.

In NSCLC, increased levels of MMP-2 have been shown to be associated with an increased propensity for both nodal and distant metastases, and increased MMP-2 in serum is related to increased metastatic spread and resistance to chemotherapy. MMP-9 overexpression is also a negative prognostic indicator in NSCLC.58

Several MMP inhibitors (MMPIs) have been developed and tested in clinical trials in NSCLC. Two recent randomized phase III trials of prinomastat showed no survival improvement when it was added to a two-drug chemotherapy regimen (carboplatin and paclitaxel or cisplatin and gemcitabine) for advanced NSCLC.59, 60 Neovastat, an MMPI extracted from shark cartilage, has shown promising evidence of activity in pretreated patients with NSCLC.61 This drug targets not only MMPs but also the VEGF signaling pathway and endothelial cell apoptosis. A phase III trial of neovastat combined with chemotherapy and radiation therapy in stage III NSCLC is ongoing. For example, BMS-275291 combined with carboplatin and paclitaxel is under evaluation in a phase III randomized trial in advanced NSCLC.62

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Protein Kinase C Inhibitors 

The protein kinase C (PKC) family of serine-threonine protein kinases is involved in signal transduction pathways that regulate growth factor response, proliferation, and apoptosis. PKC’s central role in these processes, which are closely involved in tumor initiation, progression, and response to antitumor agents, makes it a possible therapeutic target in cancer.63 One potentially attractive therapeutic intervention may be the use of selective antisense oligonucleotides to inhibit production of PKC-α. Affinitak, a selective inhibitor of PKC-α expression, is a 20-mer antisense phosphorothioate oligonucleotide to PKC-α mRNA that effectively reduces the PKC-α expression involved in several critical cell pathways. A phase II trial of affinitak with carboplatin and paclitaxel for NSCLC had a 42% overall response rate with a median survival of 19 months and an actuarial 1-year overall survival rate of 75%.64 Another phase II study demonstrated the safety and modest efficacy of affinitak in combination with cisplatin and gemcitabine in advanced NSCLC.65 However, initial results of a phase III trial of affinitak in combination with carboplatin and paclitaxel for NSCLC failed to show a survival advantage over chemotherapy alone (10 months v 9.7 months, respectively).66

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Retinoids 

Retinoids are vitamin A derivatives that are required for maintenance of normal cell growth, differentiation, and loss within epithelial tissues. Suppression of carcinogenesis by retinoids has been found in several animal models. Retinoid action is mediated through at least two classes of nuclear receptors, the retinoic acid receptor and the retinoid X receptor.67 Retinoids have been studied extensively in the chemoprevention of lung cancer with varying results.68

Bexarotene is a novel oral retinoid that selectively targets the retinoid X receptor. Unlike other retinoids, it has a favorable toxicity profile. The results of a multi-institutional phase I/II trial of oral bexarotene in combination with cisplatin and vinorelbine in advanced NSCLC were reported.69 The observed response rate was 25%, with a median survival of 14 months. Two additional phase III trials are evaluating the use of carboplatin and paclitaxel and cisplatin and vinorelbine with or without bexarotene in chemotherapy-naive patients with advanced NSCLC.

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Angiogenesis Inhibitors 

Angiogenesis is the formation of new blood vessels from pre-existing vessels, and it is essential for tumor growth, development, and metastasis.70, 71 To grow to a volume greater than 2 to 3 mm3, tumors must induce angiogenesis. A balance between proangiogenic and antiangiogenic molecules regulates tumor angiogenesis.72 One of the major regulators of the neovascularization process is VEGF, which was originally discovered as vascular permeability factor.73 Increased tumor angiogenesis, which can be identified by the overexpression of VEGF, is associated with a worse clinical outcome in NSCLC (Table 3).74, 75, 76, 77, 78, 79, 80, 81, 82, 83, 84, 85, 86, 87, 88, 89 The interaction between VEGF and its TK receptors is an important angiogenesis-regulating process.90

Table 3. Effect of VEGF Expression on Survival in Non-Small Cell Lung Cancer
First Author (year)No. of PatientsStageVEGF + Rate (%)Effect on Survival
TotalSCCAC
Ohta (1996)7442I-IV262822Reduced survival
Volm (1997)75109I-IIIA5959NIReduced survival
Imoto (1998)7691I-IIIB536138Reduced survival
Shibusa (1998)7744I61NI61Reduced survival
Giatromanolaki (1998)78120I-IV525250Reduced survival
Fontanini (1998)79107I-IIIA28NRNRReduced survival
Aikawa (1999)80112I-IIIB292835NS
Volm (1999)81168I-III595563NR
Ohta (1999)82104I858189Reduced survival
Shijubo (1999)8387I524341Reduced survival⁎
Yano (2000)84108I-IV453357NS
Masuya (2001)85104I-IIIB524758Reduced survival
Toomey (2001)8646I-IIIB858985NS
Baillie (2001)8781I-IIIA30NRNRReduced survival
Han (2001)8885I715674Reduced survival
Minami (2002)8947I30NI30Reduced survival

Abbreviations: VEGF, vascular endothelia growth factor; SCC, squamous cell carcinoma; AC, adenocarcinoma; NI, not included; NR, not recorded; NS, not statistically significant.

⁎ Only in adenocarcinoma patients.

Three isoforms of membrane-bound VEGF receptors (VEGFR) have been identified, and their roles in angiogenesis appear to be distinct. VEGFR-1 (also known as fms-like tyrosine kinase-1) has the highest binding affinity for VEGF but is capable of generating relatively little kinase activity. VEGFR-2 (also known as kinase domain region or fetal liver kinase-1) is the isotype most associated with endothelial cell proliferation and chemotaxis. The VEGFR-2 has been found in breast, ovarian, and lung tumor tissue and in glioma tissue, indicating that VEGF plays roles in these cancers and prompting researchers to identify this receptor as a potential target. VEGFR-3 (also known as fms-like tyrosine kinase-4) appears to regulate primarily lymphangiogenesis.91

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Monoclonal Antibodies Against VEGF or VEGFR 

One approach to the modulation of VEGF-mediated angiogenesis is to use antibodies against the VEGF protein itself or VEGFR.92, 93, 94 Bevacizumab is a recombinant humanized monoclonal antibody to VEGF that has been shown to inhibit growth in a variety of human cancer cell lines.95 It may also act synergistically with chemotherapy.

In a phase I trial, bevacizumab reduced serum VEGF concentrations to undetectable levels when administered at doses of ≥3 mg/kg/wk and showed no pharmacologic interactions when studied in combination with a variety of chemotherapeutic agents.96, 97 In a randomized phase II study, patients with stage IIIB/IV NSCLC were randomly assigned to undergo standard therapy with carboplatin and paclitaxel alone or with 7.5 mg/kg or 15 mg/kg of bevacizumab.98 Members of the control group (chemotherapy only) who experienced disease progression were allowed to enter the high-dose bevacizumab arm. In the high-dose arm, response rates were higher (40.0% v 21.9%) and time to progression (7.0 v 3.9 months) and median survival (17.7 v 11.6 months) were longer than they were in the 7.5-mg/kg arm. An unusual and unexpected toxicity was the development of life-threatening hemoptysis, resulting in four deaths, mainly in patients with central tumors and squamous cell disease. Less severe bleeding, including epistaxis, has been seen in trials of bevacizumab for other tumor types.

A phase III trial of bevacizumab in advanced NSCLC is currently being conducted by the ECOG. Patients with a history of hemoptysis and those with squamous cell disease are excluded from the study. Assignment is random to 15 mg/kg of bevacizumab three times per week or placebo combined with paclitaxel and carboplatin, and movement of patients from the placebo to the bevacizumab arm is not allowed. An interim toxicity analysis has been performed, and although fatal hemoptysis was seen in the bevacizumab arm, the difference was not significant between the arms.93, 94 Regular safety analyses will continue to be performed during the trial.

Bevacizumab has recently shown considerable potential in colon and renal cancers. It prolonged survival when combined with IFL (irinotecan, 5-fluorouracil, and leucovorin) in colon cancer,99 and increased the time to progression when combined with thalidomide in renal cancer.100

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VEGFR TKIs 

Semaxanib is a quinolone derivative designed to inhibit VEGFR-2 and c-kit-mediated signaling. In vivo, it inhibited the growth and metastasis of lung, colon, breast, and prostate cancers and melanoma, glioma, and sarcoma xenografts.101 In a phase I dose-ranging trial, semaxanib (4.4 to 190 mg/m2) was administered intravenously twice weekly to 63 patients with various malignancies. DLT occurred at the 190 mg/m2 dose level and consisted of headache, nausea, and projectile vomiting that was reversible within 48 hours. Semaxanib also has been studied in combination with cytotoxic drugs in patients with advanced malignancies. Numerous vascular adverse events, including transient ischemic attacks, cerebrovascular accidents, and deep venous thromboses, were seen.102 This drug was withdrawn from further development because of its adverse toxicity profile.93, 94

SU6668 is an oral TKI with multiple receptor targets including VEGFR-2, platelet-derived growth factor, and fibroblast growth factor receptor.92, 93 In preclinical testing, SU6668 inhibited the growth of established human tumor xenografts in mice. However, phase I studies once again revealed an unacceptable toxicity profile, so this agent will not be developed further.

ZD6474 is an oral inhibitor of VEGFR-2 and, to a lesser extent, EGFR. In a preclinical orthotopic model, ZD6474 showed dose-dependent inhibitory effects on tumor growth,103 and in phase I studies, it appeared to be well tolerated. With dose escalation, grade 3 thrombocytopenia, diarrhea, and rash were observed (the latter likely due to its anti-EGFR properties).104 Asymptomatic QT interval prolongation was observed on the electrocardiogram in seven of 49 patients at various dosages. A phase I study of ZD6474 was conducted in 18 Japanese patients (nine patients had NSCLC) with solid tumors refractory to standard therapy.105 Patients received a single oral dose of ZD6474 (100, 200, 300, or 400 mg) (cycle 0) followed by a 7-day observation period and then received daily dosing with ZD6474 at the same dose for 28 days (cycle 1). Further 28-day treatment cycles were administered without interruption. ZD6474 therapy was well tolerated at doses of 300 mg/d. Common adverse events in all groups were rash (n = 14), asymptomatic QT interval prolongation (n = 11), diarrhea (n = 10), proteinuria (n = 10), and hypertension (n = 7). Two of the three patients receiving 400 mg/d developed DLTs (grade 3 alanine aminotransferase elevation and grade 3 hypertension), at which point 400 mg/d was considered to exceed the maximum tolerated dose. The maximum concentration and area under the curve of ZD6474 linearly increased with the dosage. The terminal half-life ranged from 72 to 167 hours (median, 96 hours). The area under the curve at 0 to 24 hours increased by 6 to 14 times following daily dosing for 28 days. Dosages of 100 to 300 mg/d yielded protein-unbound trough concentrations of 0.08 to 0.31 μmol/L (n = 10), which exceeded the concentration that produces 50% inhibition (IC50) of ZD6474 on the kinase domain region TK (IC50, 0.04 μmol/L). Preliminary observations of tumor regression (as determined by response evaluation criteria in solid tumors) were observed in four patients with NSCLC at 200 and 300 mg/d (maintained even after dose modification from 200 to 100 mg/d in two responders and from 300 to 200 mg/d in one responder). ZD6474 (100 to 300 mg/d) was well tolerated and considered to be an appropriate dosage range for use in phase II studies of patients with NSCLC.

The tubulin-binding agent ZD6126 is a novel agent with unique antiangiogenic properties. Unlike the other agents discussed, which aim to prevent new vessel formation, ZD6126 selectively targets and induces direct damage to existing tumor endothelial cells.106, 107 ZD6126 binds to tubulin in the cytoskeleton of tumor endothelial cells and induces morphologic changes, leading to vessel occlusion and extensive central tumor necrosis. The main toxic effects, which are dose-related, include anorexia, constipation, dyspnea, fatigue, headache, nausea, vomiting, and pain.108

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Endogenous Inhibitors of Angiogenesis 

It has been postulated that primary neoplasms can inhibit the growth of their metastatic lesions through the production of tumor-derived inhibitors of angiogenesis such as endostatin and angiostatin. Endostatin inhibits endothelial cell proliferation and increases apoptosis in malignant cells.109 To establish the optimal biologic dose of endostatin, a phase I trial was conducted assessing multiple surrogate biologic end points, including serial tumor biopsies, serum sampling for ex vivo bioassays of endothelial cell proliferation, and imaging to quantitate blood flow using ultrasonography, dynamic computed tomography, and magnetic resonance imaging. The doses explored for endostatin ranged from 15 to 240 mg/m2/d by intravenous infusion. The drug was well tolerated, with no DLTs, and exhibited a linear pharmacokinetic profile. Preliminary antitumor effects have been observed in the form of tumor regression and prolonged disease stabilization in a small subset of patients.110

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Combination of Molecular Targeted Therapy 

The combination of specific inhibitors is especially appealing since such an approach may theoretically improve clinical efficacy with minimal adverse events. This is the basis for the combination of bevacizumab (directly acts on blood vessels) and erlotinib (indirectly affects blood vessels by decreasing VEGF production by tumor cells). Results of a phase I/II study of erlotinib and bevacizumab in patients with nonsquamous stage IIIB/IV NSCLC with one or more prior chemotherapy were recently presented.111 The most common adverse events were mild to moderate rash, diarrhea, and proteinuria. Preliminary data showed no pharmacokinetic interaction between the two drugs. Eight patients (20.0%; 95% CI, 7.6% to 32.4%) had partial responses and 26 (65.0%; 95% CI, 50.2% to 79.8%) had stable disease as their best response. The median overall survival for the 34 patients treated at the phase II dose was 12.6 months, with progression-free survival of 6.2 months. These data will be confirmed in phase III study.

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Cyclooxygenase-2 Inhibitors 

Cyclooxygenase-2 (COX-2) is an enzyme involved in prostaglandin production in inflammation and cancer. COX-2 is usually undetectable in most normal tissues and is induced by cytokines, growth factors, oncogenes, and tumor promoters. COX-2 expression is increased in NSCLC, especially adenocarcinoma, where it plays a key role and serves as a marker of poor prognosis. Its expression is negligible in SCLC and squamous cell cancer. The recent availability of COX-2 inhibitor medications offers a unique opportunity to interfere with the development of lung cancer and metastasis, as shown in other malignancies.112

Celecoxib, a COX-2 inhibitor, has shown preclinical synergy with several agents.113 A recent study reported increased resectability and clinical and pathologic response rates in patients with early-stage NSCLC treated with celecoxib (400 mg twice per day) in combination with carboplatin and paclitaxel in the neoadjuvant setting.114 Preliminary results of phase II study evaluating the combination of celecoxib and docetaxel in the treatment of recurrent NSCLC suggested that among 15 patients with no response to prior chemotherapy, a 15.4% response rate and a 23.1% stable disease rate were seen.115

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Discussion 

Much progress has been made in the research of molecules that are involved in proliferation, invasion, metastasis, and angiogenesis of cancer cells. One focus of interest is the role of growth factors and proangiogenic factors in cancer since therapeutic approaches for their inhibition do exist (Fig 2). Although these factors are found in most tumors, their relative significance is organ- and tumor-specific, and is regulated by the interactions among tumor cells and their microenvironment. Thus, appropriate targeted therapy for a particular tumor should be selected on the basis of the individual tumor phenotype.116, 117

  • View full-size image.
  • Figure 2. 

    Immunohistochemical analysis of growth factor and angiogenesis-related genes in primary and metastatic tumors. The expression patterns differ by histologic type and metastasis site.

Study of molecular targeted therapies necessitates formation of new study designs, including development of new end points and changes of existing endpoints. In a phase I trial for new biologic agents, an approach aimed at determining the biologically optimal dose may be more appropriate than the traditional maximum tolerated dose. In addition, in the classic phase II trial design, the main endpoint is antitumor activity, but biologic drugs often act as disease progression inhibitors. Time to progression and proportion of nonprogressors at a fixed time point may become more important clinical end points than the objective response rate. Furthermore, when possible, markers of biologic activity may serve as surrogates for tumor response. Finally, in phase III studies, classic measurable clinical benefits (survival and quality of life) will continue to be the primary end points.118

Most advanced in lung cancer research are the EGFR TKIs gefitinib and erlotinib, which have shown promising antitumor activity against cisplatin-resistant NSCLC.37, 38, 39, 40 However, phase III trials of gefitinib42, 43 and erlotinib119 in combination with chemotherapy failed to improve overall survival times, emphasizing that we do not yet know the best way to incorporate this class of agents into our current treatment regimens.

Important unanswered questions regarding targeted therapy include the following:

1.Patient selection: Further research is required to better understand the role of specific growth factors in NSCLC, since their significance in individual tumors has not yet been fully identified. Recent studies had shown that EGFR mutations are associated with a dramatic response to gefitinib and erlotinib, and that rate of mutations is very low among non responders, yet EGFR mutation status studies are not ready for purposes of patient selection. Of note is that therapy with erlotinib or gefitinib results in stable disease in a significant number of patients, yet the biological profile of these cases has not been determined. Research directions that address this issue include the finding that EGFR TKIs have a better antiitumor effect when both the tumor and the tumor-associated endothelial cells express the target receptor, as shown in animal studies120; and the finding that coexpression of both the EGFR and HER2 affected survival more than either of the receptors alone, as shown in human NSCLC tumor analyses.121, 122

2.Antitumor activity and toxic effects of biologic therapies may not be linked, in contrast to chemotherapy. Thus, biologically targeted agents have to be administered at their optimal biologic dose and not their maximal tolerated dose. In addition, biomarkers of activity have to be developed to monitor therapy with these agents.

3.Sequencing of biological and conventional therapy has to be explored further. As suggested by the INTACT II results,43 EGFR TKIs may be useful as maintenance and not in an add-on regimen. Another topic is development of biologic agents cocktails: combined anti-EGFR therapy with agents that target more than one member of the EGFR superfamily, combinations of EGFR-targeting agents, and combinations of other biologic agents with different mechanisms of action have yet to be tried clinically. It may be found that the maximal therapeutic effect is achieved by the use of a combination of biologic agents such as an EGFR inhibitor and anti-VEGF monoclonal antibody with cytotoxic drugs.122

4.Preclinical models to predict biologic agent activity: Preclinical models, especially subcutaneous implant models, have not always been able to reliably predict human clinical response. Thus, the development of patient-like orthotopic models of human lung cancer may be an important strategy for characterizing novel targeted therapies.123 In addition, collection of tissue from patients at different time points that correspond with maximum pharmacodynamic or clinical effects, or development of noninvasive imaging modalities to explore these issues will provide the best opportunity to gain insight into the reasons agents work or, more commonly, do not work.

Several randomized trials of targeted therapy in lung cancer are ongoing (Table 4). It is hoped that one or several of these approaches will prove successful and further enhance our ability to treat this still too common and deadly disease (Fig 3).

Table 4. Ongoing Randomized Trials of Molecular Targeted Therapy for Advanced Non-Small Cell Lung Cancer
AgentTargetDisease StageRegimenCompany or Group
GefitinibEGFRIVEC/RT f.b. Doc + efitinib v placeboSWOG, Intergroup
ErlotinibEGFRIVPCb ± erlotinib (TRIBUTE)Genentech
ErlotinibEGFRIVGC ± erlotinib (TALENT)Genentech
ErlotinibEGFR2ndv BSCNCIC-CTG
CetuximabEGFRIVPCb ± cetuximabImclone
CetuximabEGFRIVGC ± cetuximabImclone
CetuximabEGFR2ndDoc ± cetuximabImclone
BevacizumabVEGFIVPCb ± bevacizumabECOG
ThalidomideAngioIIIBPCb ± thalidomideECOG
BMS 275291MMPIVPCb ± BMS 275291NCIC
NeovastatMMPIVCV or PCb ± NeovastatAeterna
AffinitakPKC-αIVPCb ± affinitakLilly
AffinitakPKC-αIVGC ± affinitakLilly
BexaroteneRXRIVPCb ± bexaroteneLigand
GenasenseASO2ndDoc ± GenasenseGenta
CAICaC2ndDoc ± CAINCCTG

Abbreviations: EGFR, epidermal growth factor receptor; EC, etoposide + cisplatin; RT, radiation therapy; f.b., followed by; Doc, docetaxel; SWOG, Southwest Oncology Group; PCb, paclitaxel + carboplatin; TRIBUTE, Tarceva Lung Cancer Investigation; GC, gemcitabine + cisplatin; TALENT, Tarceva Responses in Conjunction with Paclitaxel and Carboplatin; 2nd, second-line treatment; BSC, best supportive care; NCIC-CTG, National Cancer Institute Canada Cancer Trial Group; VEGF, vascular endothelial growth factor; ECOG, Eastern Cooperative Oncology Group; Angio, angiogenesis inhibitor; MMP, matrix metalloproteinase; CV, cisplatin + vinorelbine; PKC, protein kinase C; RXR, retinoid X receptor; ASO, anti-sense oligonucleotide; NCI, National Cancer Institute; CAI, carboxyamidotriazole; CaC, calcium channel; NCCTG, North Central Cancer Treatment Group.

Adapted from http://www.cancer.gov/cancertrials.

In summary, we suggest that in the future NSCLC patients will be treated with modern chemotherapeutics and/or radiotherapy; in addition, a cocktail of biologic agents will be administered to target specific molecular markers found in the individual tumor.

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PII: S0093-7754(05)00086-2

doi:10.1053/j.seminoncol.2005.02.016

Seminars in Oncology
Volume 32, Issue 3 , Pages 315-328, June 2005

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